Abstract The primary aim of this project will be to apply recent development of genome editing technologies to generate a highly advanced ?smart? tissue-engineered construct featuring cell-based, feedback control of gene expression as a means of autoregulated drug or growth factor delivery. An important advance of this system is that cells will be programmed to automatically regulate their activity in response to environmental signals. To engineer this regulatory system, the gene regulation circuitry of stem cells (iPSCs) will be rewired to form controlled feedback loops that are activated by external stimuli, but then induce a controlled and autoregulated response. These cells will be used to form tissue-engineered constructs for in vitro and in vivo testing. The initial focus of the project will be on the creation of designer stem cells that contain artificial gene circuits that provide anti-inflammatory drug delivery in response to the environment. These cells will be engineered into stable cartilage constructs that will be implanted as a therapeutic approach for the treatment of autoimmune diseases such as rheumatoid arthritis. The creation of ?smart? cells that provide automated, long-term, feedback-controlled drug therapy represents a transformative paradigm for regenerative medicine and arthritis therapy.